CYSTEINE CONJUGATE BETA-LYASE-DEPENDENT METABOLISM OF COMPOUND-A 2-[FLUOROMETHOXY]-1,1,3,3,3-PENTAFLUORO-1-PROPENE) IN HUMAN-SUBJECTS ANESTHETIZED WITH SEVOFLURANE AND IN RATS GIVEN COMPOUND-A

Background: Sevoflurane undergoes Baralyme- or soda lime-catalyzed deg radation in the anesthesia circuit to yield compound A -[fluoromethoxy ]-1,1,3,3,3-pentafluoro-1-propene), which is nephrotoxic in rats and u ndergoes metabolism via the cysteine conjugate beta-lyase pathway in t hose animals. The objective of these experiments was to test the hypot hesis that compound A undergoes beta-lyase-dependent metabolism in hum ans. Methods: Human volunteers were anesthetized with sevoflurane (1.2 5 minimum alveolar concentration 3%, 2 l/min, 8 h) and thereby exposed to compound A. Urine was collected at 24-h intervals for 72 h after a nesthesia. Rats, which served as a positive control, were given compou nd A intraperitoneally, and urine was collected for 24 h afterward. Hu man and rat urine samples were analyzed by F-19 nuclear magnetic reson ance spectroscopy and gas chromatography-mass spectrometry for the pre sence of com pound A metabolites. Results: Analysis of human and rat u rine showed the presence of the compound A metabolites romethoxy)-1,1, 3,3,3-pentafluoropropyl]-N-acetyl-L -cysteine, (E)- and 3,3,3-tetraflu oro-1-propenyl]-N-acetyl-L-cysteine, 2-(fluoromethoxy)-3,3,3-trifluoro propanoic acid, 3,3,3-trifluorolactic acid, and inorganic fluoride, Th e presence of 2-(fluoromethoxy)-3,3,3-trifluoropropanoic acid and 3,3, 3-trifluorolactic acid in human urine was confirmed by gas chromatogra phy-mass spectrometry. Conclusions: The formation of compound A-derive d mercapturates shows that compound A undergoes glutathione S-conjugat e formation The identification of 2-(fluoromethoxy)-3,3,3-trifluoropro panoic acid and 3,3,3-trifluorolactic acid in the urine of humans anes thetized with sevoflurane shows that compound A undergoes beta-lyase-d ependent metabolism. Metabolite formation was qualitatively similar in both human volunteers anesthetized with sevoflurane, and thereby expo sed to compound A, and in rats given compound A, indicating that compo und A is metabolized by the beta-lyase pathway in both species.